Methamphetamine (METH) use is increasing in the United States. Striatal deficits in humans induced by[unreadable] METH persist after detoxification and protracted abstinence and have been associated with impairment of[unreadable] motor tasks and learning. Our lab discovered that pharmacological blockade of the striatal neurokinin-1[unreadable] receptor (NK-1R) confers protection from METH to both dopamine (DA) terminals and striatal neurons. This[unreadable] interesting and novel finding needs further investigation because it provides a therapeutic target for the[unreadable] treatment of METH abuse. Our working hypothesis is that the excessive DA released in response to METH,[unreadable] interacts with substance P-containing striatal neurons. This in turn causes excessive release of substance P[unreadable] (SP), which then acts through NK-1Rs on cholinergic and somatostatin/NOS interneurons. In the latter[unreadable] neurons, nNOS is up-regulated and excessive NO produced. We suggest that the excessive NO is what is[unreadable] causing the loss of DA-terminals and neuronal cell death in the striatum. This hypothesis will be tested by the[unreadable] following specific aims:[unreadable] Aim 1: The purpose of this aim is to test the hypothesis that SP induces striatal injury in the presence of[unreadable] METH. To this end, the selective SP agonist GR73632 will be utilized to exacerbate METH-induced striatal[unreadable] neural damage.[unreadable] Aim 2: The purpose of this aim is to test the hypothesis that the striatal NK-1 Rs signal neural damage in[unreadable] the presence of METH. To this end, the striatal NK-1 R-expressing cells will be destroyed with.the selective[unreadable] toxin SSP-saporin.[unreadable] Aim 3: The purpose of this aim is to test the hypothesis that SP modulates striatal NO production. To this[unreadable] end, neurochemical and histological methods will be utilized to establish a connection between the striatal[unreadable] NK-1 Rs and the glutamate/NO neurotoxic cascade.[unreadable] The overall, long-term goal of these studies is to define the role of the NK-1Rs in the striatal injury[unreadable] induced by METH. The information gathered may prove valuable for the treatment of METH abuse and may[unreadable] also describe a role for this receptor in the striatum.